Metabolic Overload Research Articles

Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NAD+/AMPK/SIRT1/HIF-1α Pathway.

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

Inhibition of astroglial hemichannels prevents synaptic transmission decline during spreading depression

BackgroundSpreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices.ResultsFocal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.ConclusionsTargeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.

The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.

Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.

Features of glucose-insulin homeostasis at different stages of gestation in cows.

An increase in morbidity during times of relatively high functional load on the body such as during pregnancy, confirms the role of metabolic overload in the occurrence of metabolic failures. It is better to take preventive measures such as adjusting metabolic regulation mechanisms in light of the ideal dietary composition. However, this direction is constrained by the lack of information about neurohumoral regulation. The goal of the present study was to learn more about the dynamics of changes in insulin and glucose levels in pregnant cow's blood. Research on the levels of glucose and insulin in lactating cows demonstrated that ruminants had distinct characteristics in the metabolism of carbohydrates, most notably a lessened reliance of blood glucose on insulin levels. A rise in blood glucose and insulin levels was observed as the gestational stage increased during the third trimester of pregnancy. The intensity of this insulin tolerance was contingent upon the level of productivity and glucose levels during the preceding stages of gestation.

Emerging mechanisms of obesity-associated immune dysfunction.

Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. NIH, ASTRO, AHA, Longer Life Foundation.

Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes

Hyperglycemia-induced aberrant glucose metabolism is a causative factor of neurodegeneration and cognitive impairment in diabetes mellitus (DM) patients. The pyruvate dehydrogenase kinase (PDK)–lactic acid axis is regarded as a critical link between metabolic reprogramming and the pathogenic process of neurological disorders. However, its role in diabetic neuropathy remains unclear. Here, we found that PDK1 and phosphorylation of pyruvate dehydrogenase (PDH) were obviously increased in high glucose (HG)-stimulated primary neurons and Neuro-2a cell line. Acetyl-coA, a central metabolic intermediate, might enhance PDK1 expression via histone H3K9 acetylation modification in HG condition. The epigenetic regulation of PDK1 expression provided an available negative feedback pattern in response to HG environment-triggered mitochondrial metabolic overload. However, neuronal PDK1 was decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Our data showed that the expression of PDK1 also depended on the hypoxia-inducible factor-1 (HIF-1) transcriptional activation under the HG condition. However, HIF-1 was significantly reduced in the hippocampus of diabetic mice, which might explain the opposite expression of PDK1 in vivo. Importantly, overexpression of PDK1 reduced HG-induced reactive oxygen species (ROS) generation and neuronal apoptosis. Enhancing PDK1 expression in the hippocampus ameliorated STZ-induced cognitive impairment and neuronal degeneration in mice. Together, our study demonstrated that both acetyl-coA-induced histone acetylation and HIF-1 are necessary to direct PDK1 expression, and enhancing PDK1 may have a protective effect on cognitive recovery in diabetic mice.Schematic representation of the protective effect of PDK1 on hyperglycemia-induced neuronal injury and memory loss. High glucose enhanced the expression of PDK1 in an acetyl-coA-dependent histone acetylation modification to avoid mitochondrial metabolic overload and ROS release. However, the decrease of HIF-1 may impair the upregulation of PDK1 under hyperglycemia condition. Overexpression of PDK1 prevented hyperglycemia-induced hippocampal neuronal injury and memory loss in diabetic mice.

Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy.

This article illustrates how dietary flaxseed can be used to reduce cancer risk, specifically by attenuating obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We utilize a targeted metabolomics dataset in combination with a reanalysis of past work to investigate the "metabo-bioenergetic" adaptations that occur in White Leghorn laying hens while consuming dietary flaxseed. Recently, we revealed how the anti-vitamin B6 effects of flaxseed augment one-carbon metabolism in a manner that accelerates S-adenosylmethionine (SAM) biosynthesis. Researchers recently showed that accelerated SAM biosynthesis activates the cell's master energy sensor, AMP-activated protein kinase (AMPK). Our paper provides evidence that flaxseed upregulates mitochondrial fatty acid oxidation and glycolysis in liver, concomitant with the attenuation of lipogenesis and polyamine biosynthesis. Defatted flaxseed likely functions as a metformin homologue by upregulating hepatic glucose uptake and pyruvate flux through the pyruvate dehydrogenase complex (PDC) in laying hens. In contrast, whole flaxseed appears to attenuate liver steatosis and body mass by modifying mitochondrial fatty acid oxidation and lipogenesis. Several acylcarnitine moieties indicate Randle cycle adaptations that protect mitochondria from metabolic overload when hens consume flaxseed. We also discuss a paradoxical finding whereby flaxseed induces the highest glycated hemoglobin percentage (HbA1c%) ever recorded in birds, and we suspect that hyperglycemia is not the cause. In conclusion, flaxseed modifies bioenergetic pathways to attenuate the risk of obesity, type 2 diabetes, and NAFLD, possibly downstream of SAM biosynthesis. These findings, if reproducible in humans, can be used to lower cancer risk within the general population.

The endocytosis receptor megalin: from bench to bedside.

The large (~600kDa) endocytosis receptor megalin/low-density lipoprotein receptor-related protein 2 is highly expressed at the apical membrane of proximal tubular epithelial cells (PTECs). Megalin plays an important role in the endocytosis of various ligands via interactions with intracellular adaptor proteins, which mediate the trafficking of megalin in PTECs. Megalin mediates the retrieval of essential substances, including carrier-bound vitamins and elements, and impairment of the endocytic process may result in the loss of those substances. In addition, megalin reabsorbs nephrotoxic substances such as antimicrobial (colistin, vancomycin, and gentamicin) or anticancer (cisplatin) drugs and advanced glycation end product-modified or fatty acid-containing albumin. The megalin-mediated uptake of these nephrotoxic ligands causes metabolic overload in PTECs and leads to kidney injury. Blockade or suppression of the megalin-mediated endocytosis of nephrotoxic substances may represent a novel therapeutic strategy for drug-induced nephrotoxicity or metabolic kidney disease. Megalin reabsorbs urinary biomarker proteins such as albumin, α1-microglobulin, β2-microglobulin, and liver-type fatty acid-binding protein; thus, the above-mentioned megalin-targeted therapy may have an effect on the urinary excretion of these biomarkers. We have previously established a sandwich enzyme-linked immunosorbent assay to measure the ectodomain (A-megalin) and full-length (C-megalin) forms of urinary megalin using monoclonal antibodies against the amino- and carboxyl-terminals of megalin, respectively, and reported their clinical usefulness. In addition, there have been reports of patients with novel pathological anti-brush border autoantibodies targeting megalin in the kidney. Even with these breakthroughs in the characterization of megalin, a large number of issues remain to be addressed in future research.

Enhanced protein acetylation initiates fatty acid-mediated inhibition of cardiac glucose transport.

Fatty acids (FAs) rapidly and efficiently reduce cardiac glucose uptake in the Randle cycle or glucose-FA cycle. This fine-tuned physiological regulation is critical to allow optimal substrate allocation during fasted and fed states. However, the mechanisms involved in the direct FA-mediated control of glucose transport have not been totally elucidated yet. We previously reported that leucine and ketone bodies, other cardiac substrates, impair glucose uptake by increasing global protein acetylation from acetyl-CoA. As FAs generate acetyl-CoA as well, we postulated that protein acetylation is enhanced by FAs and participates to their inhibitory action on cardiac glucose uptake. Here, we demonstrated that both palmitate and oleate promoted a rapid increase in protein acetylation in primary cultured adult rat cardiomyocytes, which correlated with an inhibition of insulin-stimulated glucose uptake. This glucose absorption deficit was caused by an impairment in the translocation of vesicles containing the glucose transporter GLUT4 to the plasma membrane, although insulin signaling remained unaffected. Interestingly, pharmacological inhibition of lysine acetyltransferases (KATs) prevented this increase in protein acetylation and glucose uptake inhibition induced by FAs. Similarly, FA-mediated inhibition of insulin-stimulated glucose uptake could be prevented by KAT inhibitors in perfused hearts. To summarize, enhanced protein acetylation can be considered as an early event in the FA-induced inhibition of glucose transport in the heart, explaining part of the Randle cycle.

1988. Piperacillin-tazobactam plus Ceftriaxone for Enterococcus faecalis endocarditis: A Single Center Experience

Abstract Background Enterococcus faecalis is a leading cause of Infective Endocarditis (IE). IE guidelines recommend combination of penicillin (PCN) or ampicillin (AMP) with ceftriaxone (CTX) in susceptible strains. OPAT allows for antibiotic continuation at home; however outpatient AMP is limited due to frequent dosing and instability. Piperacillin-tazobactam (PTZ) has similar but not identical activity against penicillin binding proteins (PBP) compared to AMP and PCN, suggesting that PTZ may be a substitute in OPAT. This study compares outcomes in those with E. faecalis IE discharged with either PTZ or PCN with CTX. Results of primary outcomes including death at 90 days and readmission at 90 days for those discharged on either PTZ or PCN in combination with CTX for E. faecalis endocarditis Results of non infectious complications and changes in antibiotic therapy in both groups post discharge Methods This single center retrospective study took place from 2016 - 2020. Adults > 18 years with AMP susceptible E. faecalis IE diagnosed using Duke’s criteria and blood or tissue cultures were included, with cultures confirming PCN susceptibility. Primary endpoint was failure of therapy at 90 days, defined as death due to any cause or infection relapse. Secondary outcomes were duration of antibiotics, change in regimen and non-infectious complications. Results Overall, 34 patients were identified, 17 in each group. Average age was 60–80 years, majority having a high Charleston comorbidity index. One did not have available AMP susceptibility but was PCN susceptible. 19 were managed surgically (65% PTZ group, 47% PCN group). Average total antibiotic course was 8.2 and 7.3 weeks in PTZ and PCN groups, with average OPAT course being 4.5 and 4.4 weeks. Primary endpoint was met in 18% patients in the PTZ group and 24% in the PCN group. Of the PCN group, 1 was admitted 4 months later due to an E. faecalis device infection, outside of primary endpoint. Nearly 80% completed antibiotic therapy with 29% in the PTZ group and 35% in the PCN group readmitted for non-infectious complications, including metabolic imbalances, stroke, volume overload and gastro-intestinal bleed. Hyperkalemia was seen in the PCN group with 3 patients requiring readmission. Seizures were not reported with combined PCN and ceftriaxone. Conclusion Similar outcomes were seen using either PTZ or PCN with CTX for treatment of enterococcal IE. Discharging patients on PCN is not always a feasible option. In these instances, PTZ could be considered as an alternative OPAT agent despite dissimilar mechanism of action compared to AMP and PCN. Disclosures All Authors: No reported disclosures.

Indications of continuous renal replacement therapy in critically ill pediatric patients

Background: Despite the increasing role of continuous renal replacement therapy (CRRT) in management of acutely ill patients requiring dialysis, the procedure remains demanding in terms of human resources and cost. Aim of the work: identification of the indications of CRRT in critically ill pediatric patients. Methods: A descriptive study of 35 pediatric patients requiring CRRT. Data regarding patients’ conditions and indications of CRRT were reported. Results: metabolic acidosis and volume overload were the most common indication of CRRT. Conclusion: CRRT is a useful therapy in critically ill children. The most frequent indications are metabolic acidosis and hypervolemia.

Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road?

The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.

Polyploidization of Hepatocytes: Insights into the Pathogenesis of Liver Diseases.

Polyploidization is a process by which cells are induced to possess more than two sets of chromosomes. Although polyploidization is not frequent in mammals, it is closely associated with development and differentiation of specific tissues and organs. The liver is one of the mammalian organs that displays ploidy dynamics in physiological homeostasis during its development. The ratio of polyploid hepatocytes increases significantly in response to hepatic injury from aging, viral infection, iron overload, surgical resection, or metabolic overload, such as that from non-alcoholic fatty liver diseases (NAFLDs). One of the unique features of NAFLD is the marked heterogeneity of hepatocyte nuclear size, which is strongly associated with an adverse liver-related outcome, such as hepatocellular carcinoma, liver transplantation, and liver-related death. Thus, hepatic polyploidization has been suggested as a potential driver in the progression of NAFLDs that are involved in the control of the multiple pathogenicity of the diseases. However, the importance of polyploidy in diverse pathophysiological contexts remains elusive. Recently, several studies reported successful improvement of symptoms of NAFLDs by reducing pathological polyploidy or by controlling cell cycle progression in animal models, suggesting that better understanding the mechanisms of pathological hepatic polyploidy may provide insights into the treatment of hepatic disorders.

Mechanisms and Treatment of Delayed Onset Muscle Soreness in Athletes - A Review

Objective: The purpose of this study is to review mechanisms for Delayed Onset Muscle Soreness (DOMS) and the pharmacological treatment options with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Method: Our review of published research literature was based on an appropriate number of subjects included in the study with a statistical power of .80 or higher and an effect size of .30 or higher. In the case of review articles, two cited references from each article where significant data were used to establish the conclusion were examined for type II error using the criteria mentioned above. Our review also includes inflammation, tissue damage, and the treatment of DOMS with both selective and non-selective NSAIDs. Results: Frequently cited mechanisms of DOMS are "mechanical strain" and "metabolic overload" within the muscle structure. The inflammation associated with DOMS is caused by eccentric exercise-induced muscle damage. NSAIDs inhibit prostaglandin synthesis and/or block cyclooxygenase and there by reduce the pain and swelling associated with inflammation. There are both selective and non-selective NSAIDs, the former being the COX-2 inhibitors (e.g., celecoxib) and the later (e.g., ibuprofen, naproxen, and aspirin). Conclusion: For the treatment of DOMS, naproxen taken at anti­inflammation levels for at least 3 days shows the most consistent results for improving the recovery rate of affected muscle.

HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes.

During progression of type 2 diabetes, pancreatic β cells are subjected to sustained metabolic overload. We postulated that this state mediates a hypoxic phenotype driven by hypoxia-inducible factor-1α (HIF-1α) and that treatment with the HIF-1α inhibitor PX-478 would improve β cell function. Our studies showed that the HIF-1α protein was present in pancreatic β cells of diabetic mouse models. In mouse islets with high glucose metabolism, the emergence of intracellular Ca2+ oscillations at low glucose concentration and the abnormally high basal release of insulin were suppressed by treatment with the HIF-1α inhibitor PX-478, indicating improvement of β cell function. Treatment of db/db mice with PX-478 prevented the rise of glycemia and diabetes progression by maintenance of elevated plasma insulin concentration. In streptozotocin-induced diabetic mice, PX-478 improved the recovery of glucose homeostasis. Islets isolated from these mice showed hallmarks of improved β cell function including elevation of insulin content, increased expression of genes involved in β cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. In response to PX-478 treatment, human islet organoids chronically exposed to high glucose presented improved stimulation index of glucose-induced insulin secretion. These results suggest that the HIF-1α inhibitor PX-478 has the potential to act as an antidiabetic therapeutic agent that preserves β cell function under metabolic overload.

Regulation of Glucose Transport in Adipocytes by Interleukin-4.

Metabolic abnormalities such as obesity, insulin resistance, and type 2 diabetes mellitus are known to be associated with adipose tissue inflammation and impaired secretion of cytokines. Anti-inflammatory cytokine interleukin-4 (IL-4) was found to promote insulin sensitivity, glucose tolerance, and reduce lipid accumulation in vivo through multiple mechanisms, including direct regulation of lipolysis in adipocytes. However, little is known about its role in adipocyte glucose metabolism. This study reveals that IL-4 upregulates glucose uptake in adipocytes without additional activation of the insulin-dependent IRS1 (insulin receptor substrate 1)-Akt (protein kinase B) pathway. Moreover, the main transcription factor STAT6 (signal transducer and activator of transcription 6), regulated by IL-4, was not involved in adipocyte glucose uptake. The proteomic results showed that IL-4 upregulates expression of proteins involved in mitochondrial biogenesis, renewal, and glucose oxidation. Our study provides a new hypothesis, explaining protective effects of IL-4 against metabolic abnormalities through activation of adipocytes glucose utilization and maintenance of mitochondrial function under metabolic overload conditions.

Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients.

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1β levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body’s responses.

Mechanisms contributing to adverse outcomes of COVID-19 in obesity.

A growing amount of epidemiological data from multiple countries indicate an increased prevalence of obesity, more importantly central obesity, among hospitalized subjects with COVID-19. This suggests that obesity is a major factor contributing to adverse outcome of the disease. As it is a metabolic disorder with dysregulated immune and endocrine function, it is logical that dysfunctional metabolism contributes to the mechanisms behind obesity being a risk factor for adverse outcome in COVID-19. Emerging data suggest that in obese subjects, (a) the molecular mechanisms of viral entry and spread mediated through ACE2 receptor, a multifunctional host cell protein which links to cellular homeostasis mechanisms, are affected. This includes perturbation of the physiological renin-angiotensin system pathway causing pro-inflammatory and pro-thrombotic challenges (b) existent metabolic overload and ER stress-induced UPR pathway make obese subjects vulnerable to severe COVID-19, (c) host cell response is altered involving reprogramming of metabolism and epigenetic mechanisms involving microRNAs in line with changes in obesity, and (d) adiposopathy with altered endocrine, adipokine, and cytokine profile contributes to altered immune cell metabolism, systemic inflammation, and vascular endothelial dysfunction, exacerbating COVID-19 pathology. In this review, we have examined the available literature on the underlying mechanisms contributing to obesity being a risk for adverse outcome in COVID-19.

Nephron overload as a therapeutic target to maximize kidney lifespan.

Kidney lifespan is a patient-oriented outcome that provides much needed context for understanding chronic kidney disease (CKD). Nephron endowment, age-associated decline in nephron number, kidney injury history and the intrinsic capacity of nephrons to adapt to haemodynamic and metabolic overload vary widely within the population. Defining percentiles of kidney function might therefore help to predict individual kidney lifespan and distinguish healthy ageing from progressive forms of CKD. In response to nephron loss, the remaining nephrons undergo functional and structural adaptations to meet the ongoing haemodynamic and metabolic demands of the organism. When these changes are no longer sufficient to maintain kidney cell homeostasis, remnant nephron demise occurs and CKD progression ensues. An individual's trajectory of glomerular filtration rate and albuminuria reflects the extent of nephron loss and adaptation of the remaining nephrons. Nephron overload represents the final common pathway of CKD progression and is largely independent of upstream disease mechanisms. Thus, interventions that efficiently attenuate nephron overload in early disease stages can protect remnant kidney cells and nephrons, and delay CKD progression. This Review provides a conceptual framework for individualized diagnosis, monitoring and treatment of CKD with the goal of maximizing kidney lifespan.